Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • As demonstrated by Bayliss Bayliss myogenic response

    2021-10-12

    As demonstrated by Bayliss Bayliss, [22] myogenic response is the ability of the blood vessels to contract in response to intraluminal pressure elevation. This is intrinsic to VSMCs, particularly in small arteries (dimeter < 200 μm), and this response is triggered by stretch. The vascular wall receptor sites and the transduction pathways for this phenomenon are not completely understood; however, these are believed to be related to stretch-induced opening of cell-membrane Ca2+ channels [23]. Recently, Darifenacin HBr polymerization within VSMCs in response to increased intravascular pressure was recognized as a novel mechanism underlying arterial myogenic mechanism [1]. Interestingly, it has been shown that undifferentiated human promyelocytic leukemia cells (HL60) that lacked FPR do not respond to shear stress, whereas expression of FPR in undifferentiated HL60 cells caused pseudopod projection and robust pseudopod retraction during fluid shear [24]. These results suggested that FPR-1 could serve as mechanosensor for fluid shear stress [24]. Because of this evidence, we subsequently postulated that FPR-1 would act as a mechanosensing like-receptor in arteries. Therefore, this receptor would be able to sense changes in pressure and be implicated in the myogenic response. Indeed, in the present study we demonstrated that pressure-induced myogenic response is lost in arteries lacking FPR-1. We suggested that FPR-1 acts as a mechansensor via the network it forms with actin filaments, and this then affects the myogenic response via actin polymerization. Not all GPCRs are necessarily a mechanical sensor. FPR has been implicated as a sensor for fluid shear stress, but other chemoattractant GPCRs, such as CXCR1 and CXCR2, did not display unique properties while exposed to shear stress [21]. Although we do not know at present why FPR-1 receptor is significantly activated by mechanical stretch, there are a few possibilities. First, differences in its response to fluid shear stress could involve differences in its signaling pathways, as neutrophil chemotaxis in response to either FMLP (FPR agonist) or IL-8 is known to display different properties. Second, diversity in the structures and expression of the receptors may also determine their responsibility to mechanical stress. It is very interesting that a decrease in FPR-1 surface expression in neutrophils, due to internalization, is direct associated with reduction of pseudopods formation [21], which is well known to be linked to actin polymerization. Therefore, we have confidence that FPR indeed contributes to the mechanosensing responses of cells within the vascular microenvironment, similar to observed in neutrophils. A similar concept was observed when AT1 receptor was recognized as a mechanosensor. In line, Zou et al. Zou et al. [34] demonstrated that although not all GPCRs were activated by stretch in the heart, AT1R was. They observed that mechanical stretch induced a conformational change in the AT1R and subsequently association with Janus kinase 2, and translocation of G proteins into the cytosol. Also, studies with PKC inhibitors have suggested a role for this kinase in the myogenic response of resistance arteries, but the underlying mechanism remains unclear [7]. Accordingly, it has been shown that the PKC inhibitors suppressed the myogenic response of rat middle cerebral arteries [3]. Because agonists for FPR lead to PKC activation, we wanted to understand if FPR-1 absence would change PKC expression. We did not observed differences in expression for this protein between WT and FPR-1 KO. However, further studies are necessary to understand if the activity of this kinase is altered by FPR-1 absence/activation. Since it has been observed that Ca2+ sensitization via phosphorylation of myosin phosphatase targeting subunit at threonine-855 by Rho kinase contributes to the arterial myogenic response [35], another possible mechanism that could be associated with FPR-1 and myogenic tone would be RhoA/ROCK activation. Here, we observed that FPR-1 activation induced MYPT1 phosphorylation (Fig. 7G), but additional experiments needs to be performed to support this hypothesis.